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The potassium channel Kv1.3 in perinatal brain injury

Award Number: R01NS110768
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/15/2019
PERIOD OF PERFORMANCE END DATE: 01/31/2024

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The potassium channel Kv1.3 in perinatal brain injury - Project Summary/Abstract Many survivors of premature birth and perinatal brain injury suffer from long-term neurological sequelae. These newborns urgently need early effective and safe interventions for neuroprotection. Our group is interested in the pharmacology of a voltage-gated potassium channel called Kv1.3 (KCNA3), which plays an important role in immune cell activation by modulating membrane potential to influence intracellular mechanisms such as Ca2+ signaling. Our group previously found that Kv1.3 is required for the pro-inflammatory state of microglia, and has provided evidence to support Kv1.3 as a therapeutic target for Alzheimer's disease and adult stroke. Recently we extended our study to a mouse model of neonatal lipopolysaccharides- sensitized hypoxic-ischemic brain injury (LPS-HI), in which activation of mononuclear phagocytes (MPs, which include microglia, monocytes, and macrophages) plays a key pathological role. This model replicates a major form of perinatal brain injury in which perinatal infection/inflammation sensitizes the brain to subsequent HI insult and augments brain injury. We showed that Kv1.3 knockout or selective pharmacological inhibition of Kv1.3 mitigates the LPS-HI brain injury. Surprisingly, while Kv1.3 RNA and protein levels were increased in MPs isolated from LPS-HI brains, whole-cell patch-clamp failed to detect significant plasma membrane Kv1.3 (PM-Kv1.3) channel activity on the MP cell surface. A logical inference is that an intracellular pool of Kv1.3, such as Kv1.3 in mitochondria, described in some tumor cell lines, is activated instead. Indeed, our recent data show increased mitochondrial Kv1.3 (mito-Kv1.3) in MPs isolated from LPS-HI brains. This discovery marks an important difference in MP activation mechanisms between the neonatal LPS-HI model and the adult models of stroke, Alzheimer's, and LPS injection, as in the latter the PM-Kv1.3 activity is significantly upregulated. Our hypothesis, therefore, is that pro-inflammatory activation of MPs, critical for neurotoxic actions in LPS-HI, requires Kv1.3, with a major contribution from mito-Kv1.3. To test this hypothesis, we will address three Aims. In Aim 1 we will use a targeted deletion approach to distinguish the respective contributions of Kv1.3 in residential microglia and Kv1.3 in invading monocytes. Such a determination will help understand dynamic neuroimmune mechanisms involving monocyte-microglia interactions and neuronal injury, about which little is known in neonatal brains. In view of our novel findings regarding mito-Kv1.3, in Aim 2 we will validate mito- Kv1.3 as a potential therapeutic target for LPS-HI brain injury. Pharmacological tools that are able to selectively target PM-Kv1.3 and mito-Kv1.3 will be tested for their efficacy in mitigating brain injury in the LPS- HI model. In Aim 3, we will further test the hypothesis that mito-Kv1.3, via regulating mitochondrial membrane potential, facilitates reprogramming of mitochondrial metabolic state to drive functional polarization. Our goal is to uncover the mechanistic link between mito-Kv1.3 and MP activation state, and design promising new therapeutic approaches to mitigate perinatal brain injury.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	6/13/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $407,070 )
2023	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/6/2023	NON-COMPETING CONTINUATION	$407,070
														Subtotal = $407,070

Issue Date FY: 2022 ( Subtotal = $421,317 )
2022	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	3/22/2022	NON-COMPETING CONTINUATION	$42,130
2022	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	1/17/2022	NON-COMPETING CONTINUATION	$379,187
														Subtotal = $421,317

Issue Date FY: 2021 ( Subtotal = $427,042 )
2021	2021	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/15/2021	NON-COMPETING CONTINUATION	$427,042
														Subtotal = $427,042

Issue Date FY: 2020 ( Subtotal = $432,398 )
2020	2020	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/10/2020	NON-COMPETING CONTINUATION	$389,159
2020	2020	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	2/7/2020	NON-COMPETING CONTINUATION	$43,239
														Subtotal = $432,398

Issue Date FY: 2019 ( Subtotal = $447,844 )
2019	2019	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/14/2019	NEW	$447,844
														Subtotal = $447,844

Grand Total All Awards = $2,135,671

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The potassium channel Kv1.3 in perinatal brain injury

Award Number: R01NS110768

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/15/2019

PERIOD OF PERFORMANCE END DATE: 01/31/2024

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